eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Galactokinase Deficiency
Updated: Sep 2, 2009
Introduction
Background
As with all hexose sugars, metabolism of ingested galactose requires an initial phosphorylation of the molecule using adenosine triphosphate (ATP). Unlike the metabolism of glucose, which ordinarily depends on the activity of hexokinase with a wide substrate-specificity to carry out this reaction, substrate-specific galactokinase activity exclusively phosphorylates galactose.1
In 1965, galactokinase deficiency was first identified in a patient who presented with cataracts and galactosuria that developed upon drinking milk. The concurrence of cataracts and galactosuria in a single individual suggested the possibility of a new type of galactosemia. This presentation differed from that of classic galactosemia in many important aspects; neither hepatosplenomegaly nor signs of mental retardation were present. When the researchers realized that the patient did not accumulate galactose-1-phosphate despite the accumulated galactose, the patient's underlying defect was deduced as the lack of the enzyme mediating 1-phosphorylation of galactose.
Pathophysiology
UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.
An appreciation of the differences between the enzyme deficiencies and their clinical manifestations is key to understanding the pathophysiology of galactokinase and galactose-1-phosphate uridyltransferase galactosemias. Whereas vomiting, failure to thrive, jaundice, hepatomegaly, and cataracts are characteristic of the onset of transferase-deficient galactosemia, cataract development is usually the only symptom observed in an infant with kinase deficiency. In people with transferase-deficient galactosemia, galactose-1-phosphate accumulates; in those with kinase deficiency, galactose-1-phosphate cannot be produced. Galactose-1-phosphate is assumed to be the substance that causes the devastating manifestations seen in people with classic galactosemia. Note that this assumption lacks definitive proof despite the intrinsic and compelling logic.
In contrast, the mechanism that produces galactose-related cataracts is understood fairly well. The lens of the eye contains the aldose reductase enzyme. When presented with accumulated galactose, this enzyme reduces the aldehydic end group and produces galactitol, the analogous sugar alcohol. This compound exerts osmotic pressure within the lens because it slowly diffuses. While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most researchers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation. The evidence favors this view because patients with galactokinase deficiency who cannot produce galactose-1-phosphate still form cataracts.
While patients who are deficient in galactokinase accumulate galactitol in the liver at rates comparable to those with transferase-deficient galactosemia, only the latter display evidence of hepatic damage. Hence, much remains to be learned about the pathophysiologic implications of galactose metabolic impairment.
Frequency
United States
Because most newborn screening programs are designed to identify transferase deficiency, accumulated galactose in submitted blood samples is missed. Accordingly, the data are insufficient to provide an accurate assessment of prevalence, although the estimated range is 1 per 50,000-100,000 live births.
International
The prevalence among certain Eastern European populations, in particular the Romani (Gypsy) population, is estimated to be approximately 1 per 10,000. The Romani people generally possess a mutation known as P28T, considered the founder mutation.
Mortality/Morbidity
The literature indicates no risk of mortality. Morbidity is limited to cataract formation in untreated individuals, although rare cases of pseudotumor cerebri have been reported. Both resolve with effective therapy. Mental retardation and hepatic damage are not associated with galactokinase deficiency.
Sex
As an autosomal recessive condition, the disorder is distributed equally between sexes.
Age
Because galactokinase deficiency is a genetic disease, it is present from conception and may be discovered at birth through the presence of congenital cataracts.
Clinical
History
- Hepatosplenomegaly at birth (reported in a single case) is not common in neonates with galactokinase deficiency.
- Failure to develop a social smile or to follow objects may represent initial signs of a visual deficit due to cataracts.
- GI symptoms associated with the ingestion of galactose are conspicuously absent.
- Growth parameters are unaffected.
- Family history is not relevant.
- Soy formula (given to the infant for other reasons) may curtail the development of cataracts and delay the consequent diagnosis of galactokinase deficiency. However, milk products introduced into the diet later will result in cataract formation.
Physical
- Cataracts may be apparent upon gross inspection of the eye.
- Opacities may be visualized during attempts at funduscopic examination.
- Vision-based developmental landmarks, such as tracking, reaching, and social smiling, may be reached late or not at all.
Causes
- Galactokinase deficiency is an autosomal recessive genetic disorder mapped to band 17q24.
- At least 20 mutations are known, of which the P28T mutation is considered the founder mutation.
- Many genetic variations of GALK1 have been identified in the patients with galactokinase deficiency.2
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| References |
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References
Cuthbert C, Klapper H, Elsas L. Diagnosis of inherited disorders of galactose metabolism. Curr Protoc Hum Genet. Jan 2008;Chapter 17:Unit 17.5. [Medline].
Park HD, Kim YK, Park KU, Kim JQ, Song YH, Song J. A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype. BMC Med Genet. Mar 24 2009;10:29. [Medline].
Berry GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr. 1995;154(7 Suppl 2):S53-64. [Medline].
Beutler E, Matsumoto F, Kuhl W, Krill A, Levy N, Sparkes R, et al. Galactokinase deficiency as a cause of cataracts. N Engl J Med. Jun 7 1973;288(23):1203-6. [Medline].
Bosch AM, Bakker HD, van Gennip AH, van Kempen JV, Wanders RJ, Wijburg FA. Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis. Dec 2002;25(8):629-34. [Medline].
Gitzelmann R. Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res. 1967;1:14-23.
Hunter M, Heyer E, Austerlitz F. The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma(Gypsy) patients across Europe. Pediatr Res. 2002;51:602-606.
Kerr MM, Logan RW, Cant JS, Hutchison JH. Galactokinase deficiency in a newborn infant. Arch Dis Child. Dec 1971;46(250):864-6. [Medline].
Levy NS, Krill AE, Beutler E. Galactokinase deficiency and cataracts. Am J Ophthalmol. Jul 1972;74(1):41-8. [Medline].
Pickering WR, Howell RR. Galactokinase deficiency: clinical and biochemical findings in a new kindred. J Pediatr. Jul 1972;81(1):50-5. [Medline].
Reich S, Hennerman J, Vetter B. An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening. Pediatr Res. 2002;51:598-601.
Sangiuolo F, Magnani M, Stambolian D. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat. 2004;23:396.
Thalhammer O, Gitzelmann R, Pantlitschko M. Hypergalactosemia and galactosuria due to galactokinase deficiency in a newborn. Pediatrics. Sep 1968;42(3):441-5. [Medline].
Further Reading
Keywords
galactosemia II, GALK deficiency, cataracts, galactosuria, hexose sugar, galactose, glucose, hexokinase, galactosemia, galactose-1-phosphate uridyltransferase galactosemias, hexokinase, galactokinase deficiency, transferase-deficient galactosemia, galactose-related cataracts
